Process for the reductive amination and selective hydrogenation of substrates containing a selected halogen

ABSTRACT

Disclosed is a process for performing a chemical reaction selected from reductive amination and hydrogenation of a first functional group in an organic feed substrate, which feed substrate comprises at least one further functional group containing a halogen atom, wherein the halogen atom is selected from the list consisting of chlorine, bromine, iodine, and combinations thereof, in the presence of hydrogen and a heterogeneous catalyst comprising at least one metal from the list of Pd, Rh, and Ru, together with at least a second metal from the list consisting of Ag, Ni, Co, Sn, Cu and Au. The process is preferably applied for the reductive amination of 2-chloro-benzaldehyde to form 2-chloro-benzyldimethylamine, as an intermediate in the production of agrochemically active compounds and microbiocides of the methoximinophenylglyoxylic ester series. Further disclosed is a composition rich in 2-chloro-benzyldimethylamine, further comprising an amount of 2-chloro-benzyl alcohol and being low in chlorotoluene isomers.

This application is the national stage filing under 35 U.S.C. § 371 ofPCT/EP2014/068083, filed Aug. 26, 2014, which claims priority toEuropean Application EP 13183017.6, filed Sep. 4, 2013, the contents ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to chemical reactions which involve thechemical conversion of a first functional group in an organic feedsubstrate, in the presence of hydrogen, whereby the organic feedsubstrate comprises at least one further functional group containing ahalogen atom other than fluorine. More particularly, the inventionrelates to the noble metal catalysed reactions selected from thereductive amination and the selective hydrogenation of only the firstfunctional group on the substrate while keeping the further functionalgroup containing the halogen atom substantially untouched and present inthe reaction product.

BACKGROUND OF THE INVENTION

The selective conversion of one functional group in a multifunctionalfeed substrate has been an area of continuous high interest throughoutthe chemical, pharmaceutical and agrochemical industry. In particular,halogen atoms are often incorporated next to other functional groups inactive ingredients or in precursors of those active ingredients.

The objective of high selectivity has often been rather elusive, becausemost processes are prone to side reactions leading to significantamounts of byproducts. These side reactions are consuming valuableamounts of feed substrate, and the byproducts are often rather useless.Some of the byproducts may also be difficult to separate from thedesired product. In cases where the desired product is an intermediatefor the production of a further derivative, some of the byproducts mayalso be disturbing for further synthesis steps because they may bereactive in such downstream process step and may lead to undesiredadditional consumption of valuable raw materials and even to undesirableand/or unacceptable end product contamination.

Multi-step synthesis protocols of complex multifunctional chemicals moreand more comprise catalytic conversion steps as these often outperformtheir stoichiometric alternatives with respect to atom efficiency andreduced waste generation. Reductive conversion steps with hydrogen gasas the reducing agent typically use metal based catalysts in order toproceed at rates of commercial interests.

Metals, however, often interfere with carbon-halogen bonds in organiccompounds. Pd in particular is for instance capable of inserting into acarbon-halogen bond. Such behaviour is desired in its use as catalyst inso-called coupling reactions. Such reactions are often used as key stepsin multi-step synthesis paths for complex organic compounds, such asactive ingredients in pharmaceutical or agrochemical industry. In acoupling reaction, a halogen containing first fragment is coupled with asecond fragment by means of a catalyst, in which the second fragment iscoupled to the first fragment at the position where the halogen wasoriginally located. The second fragment may be coupled via a largevariety of functional groups, and different versions of such couplingreactions have often received specific names, such as the Heck coupling,which is using an olefin, the Sonogashira coupling, which is using analkyne, the Suzuki coupling, which is using a boronic acid and theStille coupling, which uses an alkyl tin group. This list is far fromexhaustive, because many more different functional groups may possiblybe used for such coupling.

Insertion of a metal such as Pd into a carbon-halogen bond in thepresence of hydrogen but in the absence of a suitable fragment to coupleusually results in the displacement of the halogen atom by a hydrogenatom and hence the loss of the halogen (X) as part of the substrate.Such hydrogenolysis reaction is especially enhanced in the presence of abase which may capture the liberated acid HX. This reaction may be usedadvantageously in some applications, such as environmental treatment ofhalogenated organic pollutants.

For the production of the halogenated fragments to be used in subsequentcoupling reactions, or in case halogen atoms are required in thestructure of the final product, the insertion of the metal catalyst intothe carbon-halogen bond is not desired, as it usually leads to sidereactions and associated material losses. Not all halogens are evenlysensitive for this dehalogenation side reaction. The risk fordehalogenation is particularly high with chlorine, bromine and iodine,and much lower with fluorine-containing substrates.

A variety of methods have therefore been attempted in order to increasethe selectivity of metal catalyzed reductive aminations and selectivehydrogenations of one functional group in the presence of one or morehalogen atoms elsewhere in the substrate molecule, in particular forchlorine, bromine and iodine. The methods which are currently availablein the prior art may be subdivided into three classes.

A first method involves the addition of modifiers to the reactionmixture or working into alternative reaction media. U.S. Pat. No.6,429,335 B1 for instance discloses a process for the reductiveamination of ortho-chlorobenzaldehyde with ammonia under 140 bar ofhydrogen using Raney nickel or Raney cobalt to produce the primaryamines ortho-chlorobenzylamine. The process operates in the presence ofan amount of disodium tetraborate decahydrate (borax), optionallytogether with a small amount of bis(hydroxyethyl) sulphide, and obtainsa product selectivity of at most 95.87% wt. The main byproduct is 3.19%wt of ortho-chlorobenzyl alcohol, and only 0.1% wt of benzylamine wasfound.

Cheng et al., in “The effect of water on the hydrogenation ofo-chloronitrobenzene in ethanol, n-heptane and compressed CO₂”, AppliedCatalysis A: General 455 (2013), pp. 8-15, Elsevier, discloses theeffect of water or the use of compressed carbon dioxide as the reactionmedium on the hydrogenation of o-chloronitrobenzene to o-chloro anilineover 5% Pd or Pt on a carbon support as the catalyst. The reaction isperformed at 35° C. and under a hydrogen pressure of 40 bar. The Pdcatalysts however suffer of poor stability under these conditions.

Dan-Qian Xu et al, “Hydrogenation of ionic liquids: An alternativemethodology toward highly selective catalysis of halonitrobenzenes tocorresponding haloanilines”, Journal of Molecular Catalysis A: Chemical,235 (2005), pp. 137-142, Elsevier, addresses the same reaction. Theprocess uses Raney nickel, 5% Pt/C and 5% Pd/C catalysts in differentionic liquids, with methanol as the reference solvent. Markedly lowerdehalogenation was observed with the ionic liquid catalyst systems ascompared to the methanol reference. The drawback of the use of specialreaction media or the addition of modifiers is the extra complexitywhich needs to be built into the process.

A second method involves modifying the catalyst support in order toimprove the selectivity. US 2007/0078282 A1 performs in its Example 4the reductive amination of F-benzaldehyde with a monometallic catalystof nickel on carbon (Kataleuna 6504 K). Kratky V. et al, “Effect ofcatalyst and substituents on the hydrogenation of chloronitrobenzenes”,Applied Catalysis, A: General, 235 (2002), pp. 225-231, Elsevier,discloses a process for the liquid phase hydrogenation ofchloronitrobenzene isomers to the corresponding chloroanilines. Theprocess uses either a palladium on charcoal catalyst (Pd/C) or apalladium on sulphonated poly(styrene-co-divinylbenzene) catalyst(Pd/D). Only the Pd/D catalyst was activated, i.e. reduced prior to itsuse in the reaction. The highest selectivity obtained towards thedesired end-product was lower than 95%. Significant dechlorination wasobserved, primarily of the feed substrate over the Pd/C catalyst, and ofthe reaction product over the Pd/D catalyst.

A third method involves modifying the parent hydrogenation catalystswith additional metals, so-called promoters. Wang, Y. et al., “A greensynthesis route of ortho-chloroaniline: solvent-free selectivehydrogenation of ortho-chloronitrobenzene over Pt—Ru/Fe₃O₄/C catalyst”,Catalysis Communications 19 (2012) 110-114, Elsevier, discloses the useof Pt—Ru/Fe₃O₄/C catalyst for the selective hydrogenation of o-chloronitrobenzene at temperatures between 75 and 85° C. and a pressurebetween 17 and 40 bar. High conversion is reported with virtually nodehalogenation. U.S. Pat. No. 3,666,813 reports the use of Bi, Pb and Agmodified Pt/C catalysts and a Pb modified Pd/C catalyst for thehydrogenation of chlorinated nitrobenzenes at temperatures between 75and 100° C. and a pressure of 750 psig. While the parent Pd and Ptcatalyst showed complete (100%) dehalogenation under these conditions,the modified catalysts showed a reduced dehalogenation down to levelsbelow 5%. Mahata, N. et al., “Promotional effect of Cu on the structureand chloronitrobenzene hydrogenation performance of carbon nanotube andactivated carbon supported Pt catalysts”, Applied catalysis A: General464-465 (2013)28-34, Elsevier, shows that the presence of Cu as apromoter in a Pt catalyst with carbon nanotubes or activated carbon asthe support results in the reduction of the level of dehalogenation andan increase of the catalyst stability in the hydrogenation ofchloronitrobenzene at 120° C. and 15 bar. U.S. Pat. No. 5,512,529discloses the use of a platinum catalyst on an active carbon support andmodified by copper in the hydrogenation of halonitro compounds toaromatic haloamines.

Pt based catalysts are frequently contemplated in case of sensitivehydrogenation reactions. Examples of Pt-based multimetallic catalystsmay be found in GB 2024643, U.S. Pat. No. 3,546,297, EP 2301660 A1, andalso in the articles by Han et al.:“Effect of transition metal (Cr, Mn,Fe, Co, Ni and Cu) on the hydrogenation properties of chloronitrobenzeneover Pt/NiO2 catalysts”, Journal of Molecular Catalysis A: Chemical,vol. 209, No, 1-2, 1 Feb. 2004, pages 83-87, or by Coq et al.:“Influenceof alloying platinum for the hydrogenation of chloronitrobenzene overPtM/Al2O3 catalysts with M=Sn, Pb, Ge, Al, Zn”, Journal of MolecularCatalysis, vol. 71, 1 Jan. 1992, pages 317-333. U.S. Pat. No. 3,499,034discloses Pd—Pt catalysts which have been promoted with iron, Fe. US2001/0056035 A1 discloses a series of multimetallic catalysts which areall based on iridium, Ir, doped with one or more additional metals. In acomparative example, US 2001/0056035 A1 uses a bimetallic catalyst withplatinum in combination with copper, Cu. However, these catalysts arevery costly because of the scarcity of the platinum or of the otherprecious metals involved.

U.S. Pat. No. 5,689,021 discloses the use of a Raney Nickel catalyst,prepared from the nickel-rich crystalline precursor Ni₂Al₃, and dopedwith the addition element molybdenum to obtain Ni_(2-x)/Al₃/Mo_(x), withx=0.4±0.05, in order to selectively hydrogenate varioushalonitroaromatics to form the corresponding haloaminoaromatics. Thehydrodehalogenation side reaction was found to be virtually nonexistent.

Other chemical pathways to obtain particularly valuable polyfunctionalproducts containing halogens have also been explored.

The stoichiometric alternative to the catalytic reductive amination ofo-chloro benzaldehyde to obtain o-chloro benzyldimethylamine isexemplified by WO 2013/017611 A1, which describes a process to obtaino-chloro-benzyldimethyl amine from o-chlorobenzyl chloride anddimethylamine. The yield of the reaction was at most 95.4% of theory.The reaction was performed without involving any catalyst and a chloridesalt was obtained as an undesired byproduct. Such processes based onstoichiometric chemistry in general suffer from poor atom efficiency andproduction of large amounts of waste.

There therefore remains a need for a highly selective conversion inchemical reactions selected from the reductive amination and theselective hydrogenation of only the first functional group, on asubstrate containing at least one further functional group containing ahalogen atom. The desire is to achieve industrially acceptable reactionrates while keeping the further functional group containing the halogenatom substantially untouched and present in the reaction product.

It is an objective of the process according to the present invention tocarry out the selected chemical reaction with a low degree ofdehalogenation. Fluorine is known to be significantly less sensitive todehalogenation than the heavier and more bulky halogens chlorine,bromine and/or iodine: a fluorine atom initially present in the feedsubstrate molecule therefore has a higher likelihood to remain presentin the reaction product as compared to the other halogens. Theretherefore remains a particular need for a highly selective catalystwhich will allow a low degree of dehalogenation in a substratecontaining at least one further functional group containing chlorine,bromine and/or iodine.

The present invention aims to obviate or at least mitigate the abovedescribed problem and/or to provide improvements generally.

SUMMARY OF THE INVENTION

According to the invention, there is provided a process and aparticularly useful composition which may be prepared using the process,as defined in any of the accompanying claims.

The invention therefore provides a process for performing a chemicalreaction selected from the reductive amination and the selectivehydrogenation of a first functional group in an organic feed substrate,which feed substrate comprises at least one further functional groupcontaining a halogen atom, wherein the halogen atom is selected from thelist consisting of chlorine, bromine, iodine, and combinations thereof,in the presence of hydrogen and a heterogeneous catalyst comprising atleast one first metal selected from the list consisting of palladium,Pd, rhodium, Rh, and ruthenium, Ru, together with at least one secondmetal selected from the list consisting of silver, Ag, nickel, Ni,cobalt, Co, tin, Sn, copper, Cu, and gold, Au.

The applicants select the first metal from the list consisting ofpalladium, Pd, rhodium, Rh, and ruthenium, Ru. More preferably theapplicants use palladium as the first metal. Palladium is more readilyavailable than most of the other noble metals in the list of firstmetals, and is therefore more readily obtainable as a raw material,usually also at a lower cost for the production of the catalyst.Palladium is also a metal which is easier to recover or to recuperatefrom a spent catalyst, and to recycle into a new use. Even morepreferably, the applicants use a bimetallic catalyst with Pd beingselected as the first metal and only one metal being selected as thesecond metal. A bimetallic catalyst is easier to produce and its qualitymay be more readily controlled. Yet more preferably the applicants use abimetallic Pd/Cu catalyst, i.e. with only copper as the second metal.The applicants have found that copper is also very readily available ina suitable form for the catalyst manufacture, and also that copperreadily outperforms the other metals of the second list in at least someof the selected chemical reactions according to the present invention.

Although palladium is not recognized as a highly selective catalyst forperforming reductive aminations and hydrogenation reactions ofsubstrates containing halogens, we have found that the catalystscontaining palladium as the first metal, such as Pd—Cu bimetalliccatalysts, surprisingly combine the benefits of the high activity of thePd catalysts with a greatly improved selectivity when reacting halogencontaining substrates. The applicants believe that this advantage mayalso be present with a selected number of other first metals, asspecified, and in combination with a number of second metals, as alsospecified.

We have found that the process according to the present invention ishighly selective in performing the desired chemical conversion of thefirst functional group, while keeping the further functional groupcontaining the halogen atom substantially intact such that the halogenremains present in the reaction product. We have for instance found thatthe dehalogenation of a halide function as the further functional groupon the substrate, a side reaction which is occurring when usingmonometallic palladium catalyst, may be significantly suppressed, andessentially avoided, when using the process according to the presentinvention. The dehalogenated byproduct is typically useless, andpossibly even a nuisance. The same may apply to the halide containingbyproduct (e.g. HX) of the undesired dehalogenation reaction, which forinstance may cause corrosion to the reactor or downstream processingequipment. The side reaction thus typically represents a downgrade ofvaluable starting materials, and adds additional burden for removal ofthe byproducts from the desired reaction product or for selecting moreprecious construction materials. The process according to the presentinvention thus brings the advantage of producing a highly pure desiredreaction product, which requires much less clean-up, if any, before itmay be put to further use. The process also brings the advantage ofhighly efficient use of the starting organic substrate, with very lowdowngrade, if any, to byproducts which may be useless or undesired inthe prime reaction product, in which case the byproducts must beseparated off and typically discarded or even require additional effortsfor disposal in a responsible manner. Furthermore the process accordingto the present invention avoids the use of expensive and generally lessactive platinum as the metal in the catalyst without compromising theselectivity.

The applicants have found that the process according to the presentinvention may be particularly suitable for the reductive amination ofortho-chloro-benzaldehyde in the presence of dimethyl amine, DMA, toproduce ortho-chloro benzyl dimethyl amine, o-Cl-BDMA. The applicantshave found that the process according to the present invention mayproduce the desired o-Cl-BDMA, also known as ortho-Cl-BDMA or 2-Cl-BDMA,in very high yield and in particularly high purity, with very littlebyproducts.

The invention therefore also provides a composition comprising, asmeasured by gas chromatography, GC,

-   a) at least 98.0% wt of o-chloro-benzyl-dimethylamine, o-Cl-BDMA,-   b) at most 0.40% wt of ortho-chloro toluene, preferably the total of    all chloro toluene isomers, and-   c) at least 0.05% wt of o-chloro-benzyl alcohol.

The applicants have found that this composition is particularly suitableas an intermediate for the production of more complex structures inmulti-step synthesis routes. Such routes may lead to agrochemical orpharmaceutical active ingredients. The applicants believe that the lowpresence in the composition of ortho-chloro toluene, more generally thetotal of all chloro toluenes, in particular of the mono chloro toluenes,and preferably also of chloro dichloromethyl benzenes, also known aschloro benzalchlorides, in particular of o-chloro dichloromethylbenzene, also known as 2-chloro benzyl dichloride or ortho-chlorobenzalchloride, preferably below the detection limit in the mostappropriate analytical technique, and more preferably the total absencethereof, makes the composition highly suitable for use as raw materialin the further steps of many synthesis routes. The applicants have foundthat the compounds such as a chloro toluene, such as mono chlorotoluene, and ortho-chloro dichloromethyl benzene, are contaminants whichparticipate in downstream steps when the composition is used as anintermediate for the synthesis of complex chemical compounds. However,they do not lead to the desired compound and hence represent a loss ofvaluable reagents. The compounds which result from these contaminantsare at best inert but may also exhibit effects which are undesired inthe final composition, in which case an excessive occurrence of theseside reactions creates a need for extra purification steps in theoverall synthesis process.

The composition is in particular useful if such further steps comprisemetallation reactions such as lithiation or Grignard reactions, such asdescribed in US 2010/0113778 A1, or coupling reactions such as thereactions known as the Heck, the Sonogashira, the Suzuki or the Stillecoupling.

The applicants have found that a small amount of o-chloro-benzyl alcoholbeing present in the composition according to the present invention,which may for instance be present when the composition is obtained usingthe process according to the present invention, is of little consequencefor the further use of the composition, such as in many furthersynthesis steps and/or many uses of the products thereof.

DETAILED DESCRIPTION

The present invention will be described in the following with respect toparticular embodiments and with reference to certain drawings but theinvention is not limited thereto but only by the claims. Any drawingsdescribed are only schematic and are non-limiting. In the drawings, thesize of some of the elements may be exaggerated and not drawn on scalefor illustrative purposes. The dimensions and the relative dimensions donot necessarily correspond to actual reductions to practice of theinvention.

Furthermore, the terms first, second, third and the like in thedescription and in the claims, are used for distinguishing betweensimilar elements and not necessarily for describing a sequential orchronological order. The terms are interchangeable under appropriatecircumstances and the embodiments of the invention can operate in othersequences than described or illustrated herein.

Moreover, the terms top, bottom, over, under and the like in thedescription and the claims are used for descriptive purposes and notnecessarily for describing relative positions. The terms so used areinterchangeable under appropriate circumstances and the embodiments ofthe invention described herein can operate in other orientations thandescribed or illustrated herein.

The term “comprising”, used in the claims, should not be interpreted asbeing restricted to the means listed thereafter; it does not excludeother elements or steps. It needs to be interpreted as specifying thepresence of the stated features, integers, steps or components asreferred to, but does not preclude the presence or addition of one ormore other features, integers, steps or components, or groups thereof.Thus, the scope of the expression “a device comprising means A and B”should not be limited to devices consisting only of components A and B.It means that with respect to the present invention, the only relevantcomponents of the device are A and B. Accordingly, the terms“comprising” and “including” encompass the more restrictive terms“consisting essentially of” and “consisting of”.

The terms “ortho”, “meta” and “para”, abbreviated by o-, m-,p-respectively, are used to indicate the relative position of twosubstituents on an aromatic cycle, as defined by the International Unionof Pure and Applied Chemistry (IUPAC). Taking the standard priorityrules for functional groups and substituents into account, theirpositioning may also be referred to by numbers in chemical nomenclature.In this respect, the indication 2-, 3-, and 4-correspond to o-, m-, andp-respectively.

In an embodiment, the current invention involves the use of a Pd—Cucatalyst for the reductive conversion of halogenated substrates in thepresence of hydrogen, and in particular the reductive amination of suchsubstrates. Being a catalytically very active metal, Pd has theadvantage over Pt of being much cheaper and easier to recover.

Pd—Cu bimetallic catalysts have already found an application inenvironmental chemistry for nitrate reduction with hydrogen in wastewater treatment, where biological denitrification is no longerappropriate.

Also described in the art is the effect of the hydrogen reduction on thestructure of silica supported Pd—Cu bimetallic catalyst. A method forpreparation of such a catalyst involving consecutive deposition of Pdand Cu on a silica support has been described, but no application of thecatalyst was demonstrated.

Pd—Cu bimetallic catalysts have so far found limited applications in themanufacture of organic chemicals.

One reference describes the use of unsupported Pd—Ni, Pd—Cu and Pd—Agcatalysts for the hydrogenation of nitrobenzene to aniline. An improvedactivity was observed as compared to a palladium black reference. Thehighest activity was observed for the Pd—Ni catalyst. The introductionof a second metal was believed to lead to a better dispersion of theactive centres on the catalyst surface.

Another reference describes the preparation of an active carbonsupported Pd—Cu catalyst. Its use is demonstrated in the hydrogenationof acid halides to the corresponding aldehydes and in the stereospecificreduction of 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline.

Yet another reference reports that the alloying of copper with palladiumdeposited on carbon in the respective weight ratio of less than 0.5:1.0substantially enhances the catalytic activity of that palladium as acatalyst in the reduction of formyl benzoic acid impurities in crudephthalic acid.

Yet another reference describes the preparation and use of Pd—Cu andPt—Cu bimetallic catalysts, optionally supported on a carrier, for thehydrogenation in the gas phase of succinic or maleic acid or theiranhydrides to gamma-butyrolactone. The catalysts have the advantage ofbeing able to hydrogenate both the carbonyl group and the site of theethylenic unsaturation in a single step.

Yet another reference reports the use of Pd—Cu bimetallic nanoparticlesas a catalyst for the reduction of p-nitrophenol to p-aminophenol usingNaBH₄.

EP 0312253 A2 discloses a process for preparing tridodecylamine throughan amination reaction of dodecyl alcohol with ammonia using Cu/Ni andCu/Ni/Pd catalysts. It is shown that the presence of palladium reducesthe reaction time and enhances the yield of tridodecylamine.

In none of these references disclosing a Pd—Cu multimetallic catalyst,the effect of such catalyst on halogenated substrates, in particular inmaintaining the halogen atom in the structure of the final product, hasbeen suggested or demonstrated.

The process according to the present invention is performed in thepresence of hydrogen. The use of hydrogen (H₂) as the reducing agent ismuch favoured by the presence of a metal catalyst. Such a catalystbelieved to be instrumental in activating the molecular hydrogen byweakening the H—H bond. This functionality is not particular for, orlimited to reductive aminations, but is similar for all kind ofhydrogenation reactions in organic chemistry. Next to the activation ofH₂, the catalyst may also play a role in other reaction steps, such asthe other steps involved in the reductive amination mechanism. This roletogether with the characteristics of the reaction conditions (such asthe presence of free amine, water, the typical temperature and pressurerange, etc. . . . ) make that reductive amination catalysts are oftentailored for this specific process, especially when sensitive (e.g.multifunctional) substrates are involved. It was therefore surprising tosee that the Pd—Cu catalyst of this invention was found to show suchgood halogen retention properties for a wide array of hydrogenationreactions of halogenated substrates, and that it is thus also applicablein a much broader technical field than only in reductive aminations.

Suitable organic feed substrates for the process according to thecurrent invention are organic molecules containing at least onereducible functional group next to at least one halogen atom.

In an embodiment of the process according to the present invention, thefirst functional group is selected from the list consisting of analdehyde, a ketone, a nitro group, a carboxylic acid, a carboxylicester, a carboxylic amide, an unsaturated carbon-carbon bond, a nitrile,an imine and an oxime, and combinations thereof. Reducible functionalgroups which may suitably be hydrogenated with the Pd/Cu catalystaccording to the process of the present invention are ketones,aldehydes, nitro groups, carboxylic acids, carboxylic esters, carboxylicamides, unsaturated carbon-carbon bonds, nitrile, imine and oximegroups. Such functional groups may be present in the substrate alreadywhen this is entered into the reactor, but may also be generated in situduring the course of a chemical reaction.

In an embodiment of the process according to the present invention, thefirst functional group in the feed substrate is first converted in situby reaction with an additional reagent to form a reducible functionalgroup. In particular, ketones and aldehydes may be converted to variousintermediates, under the conditions of a reductive amination reaction,and which intermediates are subsequently hydrogenated with hydrogen tothe final product of the reaction.

The halogen atom (X) is an element from group 17 in the IUPAC periodictable dated 22 Jun. 2007. In the process according to the presentinvention, the halogen atom is selected from the list consisting ofchlorine, bromine or iodine, and combinations thereof, preferably thefurther functional group being selected from the list consisting of achloride, a bromide and an iodide. The halogen is typically attached tothe substrate by means of a covalent bond with a carbon atom (C—X bond).The carbon atom to which the halogen is attached may be either sp, sp²or sp³ hybridized.

In an embodiment, the process according to the present invention is forthe reductive amination of a halo-benzaldehyde in the presence of anitrogen containing compound, preferably the nitrogen compound beingselected from ammonia, a primary amine and a secondary amine, andmixtures thereof, preferably for the production of ortho-chloro benzyldimethyl amine, o-Cl-BDMA, by the reductive amination ofortho-chloro-benzaldehyde in the presence of dimethyl amine, DMA.

For a reductive amination, chloro benzaldehydes (ortho, meta or para)are particular interesting substrates, as they may lead to thecorresponding chloro benzylamines. Both the chloro and the aminefunctionality in these reaction products make the products of interestas further chemical building blocks, because the functionalitiesrepresent suitable points for further functionalization in subsequentsynthesis steps. The chlorine atom offers opportunities for metallationreactions, such as lithiation or Grignard reactions, while the aminegroup offers possibilities for a further reductive amination or in caseof a tertiary amine for quaternisation and conversion into othersuitable leaving groups.

Reductive amination is the reaction well known in chemistry for thesynthesis of primary, secondary or tertiary amines starting from asuitable ketone or aldehyde. The term “amination” relates to thereaction part in which an amine functionality is incorporated into thesubstrate. The term “reductive” relates to the observation, whencomparing the feed substrate and the product of a reductive aminationreaction, that a reduction has necessarily also taken place. Inchemistry, a reduction reaction refers in general to the gain ofelectrons of an atom or a molecule. In organic chemistry, reductions areusually related with the disappearance of unsaturations, such as doublebonds, from the substrate molecules. The net result of a reductiveamination of a ketone or aldehyde is the conversion of a C═O double bondinto a C—N single bond.

In an embodiment of the process according to the present invention, thereductive amination is performed in two steps, in the first stepreacting the aldehyde with the nitrogen containing compound, and in thesubsequent step introducing hydrogen and the catalyst, preferably thetwo steps being performed in the same reaction vessel. The generalmechanism of reductive aminations is believed to start with thenucleophilic addition of ammonia or a primary or secondary amine speciesto the carbonyl group of the ketone or aldehyde. Such addition may occurwith or without the aid of a catalyst. The resulting adduct, sometimesreferred to as “hemiaminal”, may react further by the elimination ofwater to the corresponding imine. The occurrence of imine formation isnot essential for the outcome of the reductive amination, and in case ofthe use of secondary amines as reagents, this even is impossible. Inthis case, enamines may be formed as intermediates.

The next step in the mechanism of the reductive amination involves areduction step. All three of an imine, a hemiaminal or an enamine may bethe substrate before and on which the reduction is taking place. Forthis step, a reducing agent is required, which itself will be oxidizedafter the reaction has been effectuated. Such as for other hydrogenationreactions, stoichiometric reagents are sometimes used for this purpose,such as for instance formic acid or hydrides such as borohydrides oraluminum hydrides, but from the point of view of atom efficiency andprocess economics, the use of hydrogen gas is particularly favourable.

In an embodiment, the process according to the present invention is forthe production of chloroaniline from nitrochlorobenzene using a catalystother than a bimetallic Pt/Cu on carbon catalyst. Halogenated nitrobenzenes are another industrially interesting class of substrates, asthey are often used as precursors to produce halogenated anilines whichfind use in the dye industry and as building blocks in multi-stepsynthesis protocols of complex active ingredients in the agrochemical orthe pharmaceutical industry. The catalyst used in the process accordingto the present invention may represent an advantageous alternative tothe expensive Pt catalysts which are often used in the art. Theapplicants have found surprisingly that a Pd/Cu catalyst, in spite ofthe reputation that Pd is supposedly much less selective than Pt, mayachieve very high selectivities in also these reactions of high economicimportance. The Pd/Cu thus represents an advantageous alternative to thePt/Cu (10:1 weight ratio) on active carbon powder catalyst proposed forthis reaction in U.S. Pat. No. 5,512,529. The applicants believe thatthis advantage may apply also to a number of other first metals otherthan Pd, in combination with a number of other second metals other thanCu.

In an embodiment of the process according to the present invention, theheterogeneous catalyst comprises the first metal at a concentration inthe range of 0.1-10.0% by weight, preferably at a concentration of atleast 0.5% by weight, more preferably at least 1.0%, even morepreferably at least 1.5%, yet more preferably at least 2.0%, preferablyat least 2.5% by weight, more preferably at least 3.0%, even morepreferably at least 3.5%, yet more preferably at least 4.0%, preferablyat least 4.5% by weight, and optionally at a concentration of at most8.0%, preferably at most 7.0%, more preferably at most 6.0% wt, evenmore preferably at most 5.0% wt, preferably at most 4.0% wt, all basedon the total weight of the catalyst. The applicants have found thatthese levels provide an advantageous balance between catalystperformance and the costs and efforts associated with the production ofthe catalyst.

In an embodiment of the process according to the present invention, theheterogeneous catalyst comprises the second metal at a concentration inthe range of 0.05-40% by weight, preferably at a concentration of atleast 0.1% by weight, more preferably at least 0.5%, even morepreferably at least 1.0% wt, yet more preferably at least 1.5% wt,preferably at least 2.0% by weight, more preferably at least 3.0% wt,even more preferably at least 4.0% wt, yet more preferably at least 4.5%by weight, preferably at least 5.0% by weight, more preferably at least5.5% wt, even more preferably at least 6.0% by weight, and optionally ata concentration of at most 35.0% by weight, preferably at most 30.0% wt,more preferably at most 25.0% wt, even more preferably at most 20.0% wt,yet more preferably at most 18.0% wt, preferably at most 16.0% wt, morepreferably at most 14.0% wt, even more preferably at most 12.0% wt, yetmore preferably at most 10.0% wt, preferably at most 9.5%, morepreferably at most 9.0% wt, even more preferably at most 8.5% wt, yetmore preferably at most 8.0% wt, preferably at most 7.5% wt, morepreferably at most 7.0% wt, even more preferably at most 6.5% wt, allbased on the total weight of the catalyst. The applicants have foundthat these levels of the second metal are also bringing an advantageouscompromise between the performance of the catalyst in the process andthe complexity and efforts in the production of the catalyst.

In an embodiment, the process according to the present invention furthercomprises the step of putting the first metal onto a support byprecipitation. The applicants have found that the precipitation methodis a very convenient method for putting a metal such as palladium onto asupport. Suitable precipitation methods for putting palladium metal ontoa support are well known in the art.

In an embodiment, the process according to the present inventioncomprises the step of putting the second metal onto a support byprecipitation. This step may be performed at the same time as puttingthe first metal onto the support, or may be performed after having putthe first metal onto the support. The applicants prefer that the secondmetal is put on the catalyst after having put the first metal onto thesupport, because they have found that the catalyst prepared as suchexhibited an even lower degree of dehalogenation when compared to acatalyst made by co-precipitation.

In an embodiment of the process according to the present invention, thechemical conversion selected from reductive amination and hydrogenationis performed in the presence of a solvent, preferably an organicsolvent, preferably the solvent comprising at least one alkanol,preferably methanol, preferably the solvent being present in a weightratio relative to the organic feed substrate in the range of 0.1-20 g/g,preferably at least 0.2 g/g, more preferably at least 0.3 g/g,optionally at most 15.0 g/g, preferably at most 10.0 g/g, morepreferably at most 5.0 g/g, even more preferably at most 4.0 g/g, yetmore preferably at most 3.0 g/g, preferably at most 2.0 g/g, even morepreferably at most 1.0 g/g. Reductive amination reaction or selectivehydrogenations according to the process of the present invention mayoccur in any suitable medium. Solvents such as water, alcohols (e.g.methanol), tetrahydrofurane (THF), dioxane, alkanes may be usedadvantageously. A solvent may bring advantages to such reductiveamination or hydrogenation reaction, such as an improved hydrogensolubility, a decreased viscosity of the reaction mixture, an improvedmixing efficiency, an improved heat transfer, etc. . . . Theconcentration of the substrate and products in such solvents may bebetween 1 and 50%, preferably between 5 and 40%, more preferably between10 and 40% by weight, based on the total reaction mixture. Highlydiluted reaction mixtures may result in poor space-time yields, while incase of highly concentrated reaction mixtures, the benefits of thesolvent may be minimized. In case the reaction substrates and productsare liquids under the reaction conditions applied, the reaction may beperformed without the addition of a solvent. One may also choose to addsmall amounts of solvents to the reaction mixture, e.g. 1 to 50%,preferably 5 to 40%, more preferably 10 to 30% by weight, relative tothe total reaction mixture. Such addition may have particular advantagessuch as to improve the catalyst performance, to decrease the autogenouspressure of the reaction mixture, to prevent phase separation to occur,etc. . . .

In case of the reductive amination of o-chloro benzaldehyde withdimethyl amine (DMA), we have found that the addition of small amountsof methanol to the reaction mixture improves the yield and operabilityof the process significantly. Without wanting to be bound by thistheory, the methanol is believed to increase the solubility of thehighly volatile amine and therefore enhancing the reaction rate in theliquid phase. Additionally, the presence of methanol may possiblyprevent the occurrence of two separate liquid phases during thereductive amination, possible because of any liberation of water as theco-product in the reaction.

In an embodiment of the process according to the present invention, theheterogeneous catalyst has been heat treated, such as prior to its usein the process, preferably at a temperature in the range of 50-500° C.,preferably at a temperature of at least 60° C., more preferably at least70° C., even more preferably at least 80° C., yet more preferably atleast 100° C., preferably at least 150° C., more preferably at least200° C., even more preferably at least 250° C., and optionally at atemperature of at most 450° C., preferably at most 400° C., even morepreferably at most 350° C., preferably the heat treatment beingperformed for at least 2 hours, more preferably 3 hours. The applicantsprefer to heat treat the catalyst at about 300° C., in air, for a periodof about 3 hours, and this after having dried the catalyst at about 60°C. for a period of 3 hrs, when no substantial further weight loss couldanymore be noticed.

The catalyst which is used in the process according to the presentinvention is preferably a bimetallic catalyst containing Pd and Cu. Themetals may occur as a true alloy or as a layered catalyst. In case of atrue alloy, no separate Pd or Cu phase may be distinguished anymore. Incase of a layered catalyst, a Pd and a Cu phase may occur as alternatingin the catalyst on a molecular level. The catalyst according to presentinvention may also contain a combination of alloyed and pure metalphases. In all cases, it is important that the two metals, Pd and Cu,are in contact with each other and do not exist as separate entities inthe reaction mixture or on a support.

In an embodiment of the process according to the present invention, thecatalyst comprises Pd and Cu in a weight ratio of Cu relative to Pd inthe range of 0.05:1.0 to 10.0:1.0, preferably at least 0.1:1.0, morepreferably at least 0.5:1.0, even more preferably at least 1.0:1.0, yetmore preferably at least 1.5:1.0, preferably at least 2.0:1.0, andoptionally at most 8.0:1.0, preferably at most 6.0:1.0, more preferablyat most 5.0:1.0, even more preferably at most 4.0:1.0, yet morepreferably at most 3.5:1.0, preferably at most 3.0:1.0, more preferablyat most 2.5:1.0. The applicants have found that with the two metals inthe ratio's as specified, the activity of the catalyst as well as thedesired reaction selectivity to the desired product are improved.

In an embodiment of the process according to the present invention, theheterogeneous catalyst has a support selected from the list consistingof carbon, alumina, silica, zeolite, clay, porous polymer and hybridpolymer, preferably a carbon support, more preferably an activatedcarbon, even more preferably an activated carbon activated by atreatment with an acid.

For the ease of handling, the catalyst is preferably supported on asolid carrier. A suitable carrier for the support of the metals in thecatalyst of the process according to the present invention is activatedcarbon, because of its large specific surface area and its good adhesionproperties. Further treatment, such as steaming, acid washing,sulphonation, or the like, may be given to the support, because thisoften enhances the adsorption properties of the activated carbon. Othercarbon carriers such as graphite or carbon nanotubes (CNB) may be usedas the support of the catalyst. Carbon supports offer the additionaladvantage that the process for recycling the metal or metals, at the endof life of the catalyst, is much simplified as compared with othersupports.

Other types of materials known by people skilled in the art may suitablybe used as the catalyst support: alumina, silica, zeolite, clay, porouspolymer and hybrid polymer, and combinations thereof.

The total metal loading on the catalyst support may be in the range of0.1 to 40% by weight, more preferably at least 0.2%, more preferably0.5%, most preferably 1.0%, and optionally at most 35% by weight,preferably at most 30%, more preferably at most 25%, whereby the levelsare expressed relative to the total weight of the catalyst.

The supported catalyst may occur in a form which is most suitable anddesired for the process, such as a powder, a granule, an extrudates, orcombinations thereof. With a powder catalyst, the catalyst may after usebe separated from the reaction mixture by filtration. With granulesand/or extrudates, the catalyst and the reaction mixture may beseparated from each other by simple draining of the reactor vesselcontaining the catalyst, which may for instance be arranged in a fixedbed arrangement.

In an embodiment of the process according to the present invention, theheterogeneous catalyst has a metal area, as measured by carbon monoxidechemisorption of at least 0.5 m²/g, preferably at least 1.0 m²/g, morepreferably at least 2.0 m²/g, even more preferably at least 3.0 m²/g,yet more preferably at least 4.0 m²/g, optionally at most 12.0 m²/g.

In an embodiment of the process according to the present invention, theheterogeneous catalyst has been pre-reduced prior to the step ofcontacting the catalyst with the organic feed substrate, preferably bysubjecting the catalyst at a temperature of at least 120° C., preferablyat least 140° C. to a hydrogen atmosphere of at least 5 bar gauge,preferably at least 8 bar gauge during a period of at least 30 minutes,preferably at least 45 minutes, preferably the pre-reduction beingperformed with the catalyst being in contact with an organic liquidphase, preferably an alkanol, more preferably methanol. The applicantsprefer to preform this pre-reduction step with the catalyst in contactwith methanol, at a temperature of about 150° C., and under a hydrogenpartial pressure of about 10-11 bar absolute, and this for a period ofabout one hour. The applicants have found that this pre-reduction stepallows the catalyst to exhibit its desired advantageous performance fromvery early on in starting the process.

In an embodiment of the process according to the present invention, atleast 80% of the feed substrate is retaining the at least one furtherfunctional group after the conversion, preferably at least 85%, morepreferably at least 90%, even more preferably at least 95%, preferablyat least 97%, more preferably at least 98%, even more preferably atleast 99.0%, preferably at least 99.4%, more preferably at least 99.5%,even more preferably at least 99.6% of the feed substrate is retainingthe at least one further functional group after the conversion. Theapplicants have found that these results are readily achievable with thecatalyst of the process according to the present invention.

In an embodiment of the process according to the present invention, thechemical conversion selected from reductive amination and hydrogenationis performed at a H₂ partial pressure in the range of 0.01-250 bargauge, preferably at least 0.1, more preferably at least 1, even morepreferably at least 5.0 bar gauge, even more preferably at least 10.0bar gauge, yet more preferably at least 20 bar gauge, preferably atleast 30 bar gauge, more preferably at least 40 bar gauge, even morepreferably at least 50 bar gauge, and optionally at most 200 bar gauge,preferably at most 150 bar gauge, more preferably at most 100 bar gauge,even more preferably at most 80, yet more preferably 70, and preferablyat most 60 bar gauge.

In an embodiment of the process according to the present invention, thechemical conversion selected from reductive amination and hydrogenationis performed at a temperature in the range of 0-300° C., preferably atleast 10° C., more preferably at least 20° C., even more preferably atleast 30° C., yet more preferably at least 40° C., preferably at least60° C., more preferably at least 80° C., and even more preferably atleast 90° C., and optionally at most 250° C., preferably at most 200°C., more preferably at most 180° C., even more preferably at most 150°C., yet more preferably at most 130° C., preferably at most 120° C.,more preferably at most 110° C., even more preferably at most 100° C.

In an embodiment, the process according to the present invention isperformed in continuous mode. The applicants have found that thecatalyst itself, as well as its performance, may be arranged to befairly stable over time, such that the process is highly suitable for acontinuous operating mode. This brings significant advantages in termsof production rate, volumetric efficiency of the process equipment,control equipment, steadiness of performance, operator attention andintervention frequency, automation capabilities, many of which representsignificant advantages to the process owner.

The applicants have found that the process according to the presentinvention may also be performed in batch mode. The applicants have foundthat the catalyst, upon separation from the reaction medium after afirst performance of the process, may readily be reused in a secondperformance of the process, preferably without any intermediatetreatment. The applicants have found that at least 5, preferably atleast 10, and more preferably at least 15 reuse cycles may be performedwith the same catalyst in the process according to the presentinvention. The applicants have found that some metal may leach from thecatalyst during the early performances of a fresh catalyst in theprocess according to the present invention, but that such metal leachingis at a level which is substantially insignificant in terms of amount ofmetal lost from the catalyst, and also does not cause any substantialloss of performance of the catalyst.

In an embodiment, the process according to the present invention furthercomprises the purification of the converted substrate, preferably by thedistillation of the reaction product, for reducing the content of atleast one compound selected from a reaction byproduct, a feed impurity,a solvent, and unreacted feed substrate.

In an embodiment wherein the process according to the present inventionis used for the production of ortho-chloro benzyl dimethyl amine,2-Cl-BDMA, the process is further comprising subjecting the 2-Cl-BDMA toa Grignard reaction, comprising for example in a first step thepreparation of a Grignard reagent in which a magnesium atom isintroduced in between the benzene ring and the chlorine atom, followedby a second step wherein the Grignard reagent is reacted with an oxalicacid dialkyl ester.

In an embodiment wherein the process according to the present inventionis used for the production of ortho-chloro benzyl dimethyl amine,2-Cl-BDMA, the process is further comprising the conversion of 2-Cl-BDMAinto o-chloromethylphenylglyoxylic esters by a method such as describedin US 2010/113778 A1. o-Chloromethylphenylglyoxylic esters are importantintermediates for preparing agrochemically active compounds ormicrobicides of the methoximinophenylglyoxylic ester series. Moreparticularly, US 2010/113778 A1 describes the production ofstrobilurines, a type of fungicides that are stated to inhibit therespiratory system of the fungi, and of which Kresoxim-methyl andDimoxystrobin are named and exemplified as particularly interestingfamily members. In a further embodiment therefore, the process accordingto the present invention further comprises the production of a fungicidecomposition containing a methoximinophenylglyoxylic ester derivativedfrom 2-Cl-BDMA, in particular derived from the composition according tothe present invention, as well as further comprising the step of usingthe fungicide composition containing the ester for treating a substrate.The fungicide composition may be solid, such as a powder, or liquid, inwhich the ester may be dissolved or dispersed. The step of using thefungicide composition may be performed by any one of the methods knownin the art, and combinations thereof, such as by spraying, by brushing,by pooring, by dusting, by mixing and the like, including combinationsthereof.

In an embodiment of the composition according to the present invention,the composition comprises at least 98.5% wt of2-chloro-benzyl-dimethylamine, preferably at least 99.0% wt, morepreferably at least 99.1% wt, even more preferably at least 99.2% wt,yet more preferably at least 99.3% wt of 2-chloro-benzyl-dimethylamine.The higher the content in 2-chloro-benzyl-dimethylamine, the moreadvantageously the composition may be applied in its desiredapplication, such as a conversion to a further chemical derivative.

In an embodiment, the composition according to the present inventioncomprises at most 0.04% wt of 2-chloro-dichloromethyl benzene,preferably at most 0.030% wt, more preferably at most 0.020% wt, evenmore preferably at most 0.015% wt, preferably at most 0.010% wt, morepreferably at most 50 ppm by weight, even more preferably at most 10ppm, of 2-chloro-dichloromethyl benzene. This component may represent anadditional burden in applying the composition, such as generatingcorrosive components in subsequent reactions, and/or leading toundesired byproducts in subsequent conversions. The lower the content of2-chloro-benzylchloride, the more advantageously the composition may beapplied in its desired application, such as a conversion to a furtherchemical derivative.

In an embodiment, the composition according to the present inventioncomprises at least 0.07% wt of 2-chloro-benzyl alcohol, preferably atleast 0.09% wt, more preferably at least 0.10% wt, even more preferablyat least 0.12% wt, yet more preferably at least 0.15% wt of2-chloro-benzyl alcohol.

In an embodiment, the composition according to the present inventioncomprises at most 1.0% wt of 2-chloro-benzyl alcohol, preferably at most0.80% wt, more preferably at most 0.60% wt, even more preferably at most0.50% wt, yet more preferably at most 0.40% wt of 2-chloro-benzylalcohol.

The applicants have found that the 2-chloro-benzyl alcohol mayacceptably be present in the composition without jeopardising oraffecting the performance of the composition in many of itsapplications, such as particular conversions into further chemicalderivatives, in particular those conversions and uses which have beendescribed in more detail elsewhere in this document. The applicants havefound that there is for many of such applications little to no need forthe removal of any 2-chloro-benzyl alcohol which may be present in thecomposition, in particular not when it is present at the levels asspecified. This represents an advantage because the removal of2-chloro-benzyl alcohol from the prime product2-chloro-benzyl-dimethylamine, and this to very low levels, may bringsignificant additional complexity to the process.

In an embodiment, the composition according to the present inventioncomprises at most 0.20% wt of 2-chloro-benzaldehyde, preferably at most0.15% wt, more preferably at most 0.10% wt, preferably at most 0.05% wt,more preferably at most 0.020% wt, even more preferably at most 0.010%wt, preferably at most 50 ppm by weight, more preferably at most 10 ppm,even more preferably at most 5 ppm, yet more preferably at most 1 ppm byweight, as determined by gas chromatography, GC, if needed assisted bymass-spectrometry. This 2-chloro-benzaldehyde does not contribute tomany of the applications of the composition. A presence at a lower levelof this component therefore represents an improved effectiveness andbrings improved efficiencies in the further use and application of thecomposition.

In an embodiment, the composition according to the present inventioncomprises at most 0.40% wt of 4-chloro-benzyl dimethylamine, preferablyat most 0.30% wt, more preferably at most 0.20% wt, even more preferablyat most 0.10% wt of 4-chloro-benzyl dimethylamine, preferably at most0.05% wt, more preferably at most 0.020% wt, even more preferably atmost 0.010% wt, preferably at most 50 ppm by weight, more preferably atmost 10 ppm, even more preferably at most 5 ppm, yet more preferably atmost 1 ppm by weight, as determined by gas chromatography, GC. Theapplicants have found that this component may represent an additionalburden in applying the composition, such as in subsequent reactions,and/or may lead to undesired byproducts in subsequent conversions whichin addition may be rather difficult to separate from the desired productof such conversion. The lower the content of 4-chloro-benzyldimethylamine, the more advantageously the composition may be applied inits desired application, such as a conversion to a further chemicalderivative.

In an embodiment, the composition according to the present inventioncomprises at most 0.35% wt of ortho-chloro toluene, preferably at most0.30% wt, more preferably at most 0.20% wt, even more preferably at most0.10% wt of ortho-chloro toluene, preferably at most 0.05% wt, morepreferably at most 0.03% wt, even more preferably at most 0.01% wt,preferably at most 0.05% wt, more preferably at most 0.020% wt, evenmore preferably at most 0.010% wt, preferably at most 50 ppm by weight,more preferably at most 10 ppm, even more preferably at most 5 ppm, yetmore preferably at most 1 ppm by weight, as determined by gaschromatography, GC. Preferably the specified levels apply to the totalof all chloro toluene isomers together. The applicants have found thatthis component, and also its isomers, may represent an additional burdenin applying the composition, such as in subsequent reactions, and/or maylead to undesired byproducts in subsequent conversions which in additionmay be rather difficult to separate from the desired product of suchconversion. The lower the content of chloro toluenes, in particular ofortho-chloro toluene, the more advantageously the composition may beapplied in its desired application, such as a conversion to a furtherchemical derivative.

In an embodiment, the composition according to the present inventioncomprises at most 0.40% wt of benzyl dimethyl amine, preferably at most0.30% wt, more preferably at most 0.20% wt, even more preferably at most0.10% wt of benzyl dimethyl amine, preferably at most 0.05% wt, morepreferably at most 0.020% wt, even more preferably at most 0.010% wt,preferably at most 50 ppm by weight, more preferably at most 10 ppm,even more preferably at most 5 ppm, yet more preferably at most 1 ppm byweight, as determined by gas chromatography, GC. This benzyl dimethylamine does not contribute to many of the applications of thecomposition. A presence at a lower level of this component thereforerepresents an improved effectiveness and brings improved efficiencies inthe further use and application of the composition.

In an embodiment, the composition according to the present inventioncomprises at most 0.40% wt of 2-dimethylaminobenzyl dimethylamine,preferably at most 0.30% wt, more preferably at most 0.20% wt, even morepreferably at most 0.10% wt of 2-dimethylaminobenzyl dimethylamine,preferably at most 0.05% wt, more preferably at most 0.020% wt, evenmore preferably at most 0.010% wt, preferably at most 50 ppm by weight,more preferably at most 10 ppm, even more preferably at most 5 ppm, yetmore preferably at most 1 ppm by weight, as determined by gaschromatography, GC. This 2-dimethylamino-benzyldimethylamine does notcontribute to many of the applications of the composition. A presence ata lower level of this component therefore represents an improvedeffectiveness and brings improved efficiencies in the further use andapplication of the composition.

In an embodiment, the composition according to the present inventioncomprises at most 0.40% wt of benzaldehyde, preferably at most 0.30% wt,more preferably at most 0.20% wt, even more preferably at most 0.10% wtof benzaldehyde, preferably at most 0.05% wt, more preferably at most0.020% wt, even more preferably at most 0.010% wt, preferably at most 50ppm by weight, more preferably at most 10 ppm, even more preferably atmost 5 ppm, yet more preferably at most 1 ppm by weight, as determinedby gas chromatography, GC. This benzaldehyde does not contribute to manyof the applications of the composition. A presence at a lower level ofthis component therefore represents an improved effectiveness and bringsimproved efficiencies in the further use and application of thecomposition.

In an embodiment, the composition according to the present invention isproduced by the process according to the present invention. Theapplicants have found that the process according to the presentinvention is particularly suitable for producing the composition,because the process is able to provide a high reaction rate andconversion to the desired 2-chloro-benzyl-dimethylamine, which achieveslow levels of the unconverted feed substrate 2-chloro-benzaldehyde, andthanks to the high selectivity of the catalyst as specified, with lowpresence of less desired byproducts, such as 2-chloro-benzyl alcoholand/or benzyl dimethyl amine and/or 2-dimethylamino-benzyldimethylamine.In addition, the process according to the present invention for theproduction of 2-chloro-benzyl-dimethylamine has little to no presence ofthe other undesired components 2-chloro-benzylchloride and/or4-chloro-dimethylbenzylamine and/or chloro toluene isomers, inparticular ortho-chloro toluene. The composition according to thepresent invention as obtainable by the process according to the presentinvention is thus particularly suitable for use in many of itsapplications, such as particular conversions into further chemicalderivatives, in particular those conversions and uses which have beendescribed in more detail elsewhere in this document.

Analyticals

For analysing the composition according to the present invention, aswell as in the monitoring of the process according to the presentinvention, the applicants prefer to use the following gaschromatography, GC, analytical method.

The GC apparatus is preferably an Agilent 6890N with split injector anda flame ionization detector (FID). The apparatus is equipped with acapillary column coated with a stationary phase type CP-Sil 5 CB withdimensions 60 m×320 μm×5.0 μm. The applicants prefer to use an injectortemperature of 280° C., an injector volume of 1 μliter and a split ratioof 1/30. The applicants prefer to use helium as the carrier gas, with aflow of 2 ml/min at constant flow. The oven is given a temperatureprogram of holding for 3 minutes at 60° C., and subsequently ramping upthe temperature at a rate of 20° C. per minute up to 290° C., at whichtemperature the column is kept for an additional 15 minutes. The FIDdetector is kept at 300° C., and fed with a hydrogen flow of 45 ml/minand an air flow of 450 ml/min. Make up gas, preferably nitrogen, andcolumn flow together are set at a total of 45 ml/min.

The applicants have found that the following components may readily beidentified by specific retention peaks: methanol, DMA, TMA,ethylbenzene, benzaldehyde, benzyl dimethyl amine, ortho-chlorobenzaldehyde, ortho-chloro benzylalcohol, ortho-chloro benzyl dimethylamine, para-chloro benzyl dimethyl amine, ortho (dimethylamino) benzyldimethyl amine. The applicants have further found that this GC techniquemay readily be assisted with the addition of mass-spectrometry, such asfor determining concentrations in the lower levels down to 1 ppm wt oreven below.

Depending on the sample, the sample may be diluted up to 10 times inisopropanol. Preferably 1% of the internal standard is added, upon whichthe sample is preferably vigorously mixed for at least one minute, andafter which 1 μl of sample may be injected into the gas chromatograph.

EXAMPLES

Where percentages are given in these examples, they mean percentages inweight, unless otherwise specified.

Example 1 Preparation and Activation of the Pd/Cu Catalyst

10 g of a 5% wt palladium on carbon catalyst, as this is commerciallyavailable under the reference E196NN/W from the company Evonik, wasstirred in 300 mL of an aqueous solution of copper nitrate (6.7 g/L). 50ml of an aqueous solution of sodium carbonate (38.4 g/L) were addedslowly under vigorous stirring at room temperature over a period of 3minutes. This solution was then stirred for another 15 minutes at roomtemperature and 15 minutes at a temperature of 75° C. The catalyst wasthen filtered off and dried in an oven at the temperature of 60° C.until complete dryness. After that, the catalyst was calcined in air at300° C. for 3 hours and reduced in methanol at a temperature of 150° C.and under a hydrogen partial pressure of 10 bar. Afterwards, thecatalyst was filtered off until a paste was obtained. This paste wascontaining 5.67% of palladium and 13.7% of copper.

Example 2 Reductive amination of 2-chloro-benzaldehyde with DMA toproduce 2-Cl-BDMA

A 300 mL autoclave (Parr) was loaded with 90 g of 2-chloro benzaldehyde(Sigma Aldrich) and 54 g of methanol (industrial grade). The reactor wassealed and the gas phase was flushed three times with nitrogen. Then, 40g of dimethyl amine was added to the reaction mixture, causing thetemperature to increase to 55° C. in 5 minutes time. The reactor wasfurther heated in 10 minutes to the desired temperature of 80° C. Thereactor pressure was set to 10 bar by the addition of nitrogen gas.Stirring was then continued for 60 minutes at a temperature of 80° C.and a pressure of 10 bar. Then, the reactor was cooled to 30° C. anddegassed. 0.1 g of the catalyst from example 1 was added to theautoclave. The autoclave was heated in 15 minutes to 90° C. and hydrogenwas added to a final pressure of 55 bar. The hydrogenation reaction wasallowed to proceed for 5 h at 90° C. Then the reactor was cooled downand degassed at room temperature. A sample was taken and analyzed by GCand ICP The catalyst was then filtered and re-used again in a repeatexperiment using the same conditions, in a second run.

The tables below report the results obtained, all expressed in weightunits relative to the total weight of the reaction product disregardingwater, methanol and any residual dimethylamine that might still bepresent.

Product of the first reaction:

2-Cl-BZA BDMA 2-Cl-BDMA DMA-BDMA 2-Cl-BOH Others Pd Cu (%) (%) (%) (%)(%) (%) (ppm) (ppm) Nd 0.04 99.14 0.16 0.47 0.19 <0.5 7.42Product of the second run:

2-Cl-BZA BDMA 2-Chloro- DMA- 2-Chloro- Others Pd Cu (%) (%) BDMA (%)BDMA (%) benzylOH (%) (%) (ppm) (ppm) 0.03 0.08 98.82 0.17 0.73 0.17<0.5 1.56

-   Legend:-   Nd Not detected-   2-Cl-BZA 2-chloro-benzaldehyde-   BDMA Benzyl dimethylamine-   2-Cl-BDMA 2-chlorobenzyl dimethylamine-   DMA-BDMA 2-dimethylaminobenzyl dimethylamine-   2-Cl-BOH 2-chlorobenzyl alcohol

It is observed that the selectivities and yields remained substantiallythe same for both runs, and that they were exceptionally high in favourof the desired product 2Cl-BDMA. It may be further observed that someleaching of Cu metal occurred in the first run, but that this wasstrongly reduced already during the second run.

Example 3 Reductive Amination of Ortho-Chloro-Benzaldehyde with DMA

Methanol (27 g), ortho-chloro-benzaldehyde (2-Cl-BZA, 90 g) anddimethylamine (DMA, 37 g) were introduced into a 300 ml high pressurereactor. Dimethylamine was introduced by connecting the autoclave with abomb containing liquid DMA. Nitrogen was fed into the reactor until apressure of 10 barg was reached. The mixture was heated to 80° C. andwas kept at this temperature under constant stirring (450 rpm) for 1hour. The mixture was cooled to room temperature and the reactor wasvented. The catalyst, containing 3% wt Pd and 7% wt Cu on carbon, wasprepared by slurrying a 3% wt Pd/C catalyst in demineralised water.Then, an appropriate amount of CuCl₂ aqueous solution was added to theslurry. Subsequently, aqueous NaHCO₃ was added until the pH reached7-7.2. The resulting slurry was then heated, and a chemical reductionwas performed by means of adding sodium formate. During this procedure,gas was released from the slurry and the temperature was furtherincreased to 95° C. Then, the slurry was cooled, decanted or filtered,and washed with fresh demineralised water. Prior to use in theexperiment the catalyst was reduced at 180° C. under hydrogen at 10 barghydrogen for 1 hour.

This catalyst was introduced into the cooled and vented reaction mixtureand hydrogen was fed into the reactor until a pressure of 70 barg wasreached. The mixture was heated to 100° C. and was kept at thistemperature under constant stirring (900 rpm) for 1 hour. The exact sameprocedure was performed with a 5% Pd on carbon catalyst which had notbeen pre-reduced.

The results are reported in the following table:

Selectivity (%) Conversion 2Cl- 2-Cl- Catalyst (%) BDMA BDMA BOH BOHOthers Pd on C 99.9 33.4 45.8 0.16 <0.05 20.6 Pd/Cu on 99.9 98.25 0.460.37 <0.05 0.86 carbon Legend (further to the symbols defined hereinabove): BOH Benzyl alcohol

Example 4 Reductive amination of 4-chloro-benzaldehyde to4-chloro-benzyl dimethylamine

Methanol (27 g), para-chloro-benzaldehyde (4-Cl-BZA, 90 g) anddimethylamine (DMA, 37 g) were introduced into a 300 ml high pressurereactor. Dimethylamine was introduced by connecting the autoclave with abomb containing liquid DMA. Nitrogen was fed into the reactor until apressure of 10 barg was reached. The mixture was heated to 80° C. andwas kept at this temperature under constant stirring (450 rpm) for 1hour. The mixture was cooled to room temperature and the reactor wasvented. The catalyst, containing 3% wt Pd and 7% wt Cu on carbon, andwhich was reduced prior to the experiment at 180° C. under hydrogen at10 barg for 1 hour, was introduced into the reaction mixture andhydrogen was fed into the reactor until a pressure of 70 barg wasreached. The mixture was heated to 100° C. and was kept at thistemperature under constant stirring (900 rpm) for 1 hour. The exact sameprocedure was performed with a 5% Pd on carbon catalyst, which was notpre-reduced.

The results are reported in the following table:

Selectivity (%) Catalyst Conversion (%) 4-Cl-BDMA BDMA Others Pd/C 83.130.2 48.3 20.6 Pd/Cu on C 75 96.4 1.9 0.86 Legend (further to thesymbols defined herein above): 4-Cl-BDMA 4-chlorobenzyl dimethylamine

Example 5 Reductive amination of 2,4-dichloro-benzaldehyde to2,4-dichlorobenzyl dimethylamine

Methanol (27 g), 2,4-dichloro-benzaldehyde (2,4-Cl-BZA, 90 g) anddimethylamine (DMA, 30 g) were introduced into a 300 ml high pressurereactor. Dimethylamine was introduced by connecting the autoclave with abomb containing liquid DMA. Nitrogen was fed into the reactor until apressure of 10 barg was reached. The mixture was heated to 80° C. andwas kept at this temperature under constant stirring (450 rpm) for 1hour. The mixture was cooled to room temperature and the reactor wasvented. The catalyst, containing 3% wt Pd and 7% wt Cu on carbon, whichwas reduced prior to the experiment at 180° C. under hydrogen at 10 bargfor 1 hour, was introduced into the reaction mixture and hydrogen wasfed into the reactor until a pressure of 70 barg was reached. Themixture was heated to 100° C. and was kept at this temperature underconstant stirring (900 rpm) for 15 minutes. The exact same procedure wasperformed with a 5% Pd on carbon catalyst, which was not pre-reduced.

The results are reported in the following table:

Selectivity (%) Catalyst Conversion (%) 2,4-Cl-BDMA BDMA Others Pd/C78.3 30.5 48.2 21.3 Pd/Cu on C 68.3 96.8 1.9 1.2 Legend (further to thesymbols defined herein above): 2,4-Cl-BDMA 2,4-chlorobenzyldimethylamine

Example 6 Hydrogenation or 2-Chloro-benzaldehyde to 2-Chloro-benzylalcohol

Water (150 g), ortho-chloro-benzaldehyde (2-Cl-BZA, 30 g) wereintroduced into a 300 ml high pressure reactor, together with thecatalyst containing 3% wt Pd and 7% wt Cu on carbon (0.11 g). Hydrogenwas fed into the reactor until a pressure of 20 barg was reached. Themixture was heated to 100° C. and was kept at this temperature underconstant stirring (900 rpm) for 2 hours. The exact same procedure wasperformed with a 5% Pd on carbon catalyst, which was not pre-reduced.

The results are reported in the following table:

Selectivity (%) Catalyst Conversion (%) 2-Cl-BOH BOH Toluene BZA OthersPd on C 40.25 12.50 35.39 0.70 16.87 34.54 Pd/Cu on 37.5 58.74 15.6111.96 4.87 8.82 C Legend (further to the symbols defined herein above):2-Cl-BOH 2-chloro-benzyl alcohol BZA Benzaldehyde

Example 7 Hydrogenation or 2-Chloro-nitrobenzene to 2-Chloro-aniline

Ethanol (150 g), ortho-chloro-nitrobenzene (30 g) were introduced into a300 ml high pressure reactor, together with the catalyst containing 3%wt Pd and 7% wt Cu on carbon (0.11 g). Hydrogen was fed into the reactoruntil a pressure of 20 barg was reached. The mixture was heated to 50°C. or to 100° C. and was kept at this temperature under constantstirring (900 rpm) for 2 hours. The exact same procedure was performedwith a 5% Pd on carbon catalyst, which was not pre-reduced.

The results are reported in the following table:

Selectivity (%) Catalyst Temperature Conversion (%) 2-Cl-aniline AnilinePd on C 50° C. 97.3 66 34 Pd/Cu on C 50° C. 11.1 100 0 Pd/Cu on C 100°C.  97.7 93 7

Example 8 Reductive amination of 4-bromo-benzaldehyde to 4-bromo-benzyldimethylamine

Methanol (27 g), para-bromo-benzaldehyde (4-Br-BZA, 90 g) anddimethylamine (DMA, 27 g) were introduced into a 300 ml high pressurereactor. Dimethylamine was introduced by connecting the autoclave with abomb containing liquid DMA. Nitrogen was fed into the reactor until apressure of 10 barg was reached. The mixture was heated to 80° C. andwas kept at this temperature under constant stirring (450 rpm) for 1hour. The mixture was cooled to room temperature and the reactor wasvented. The catalyst, containing 3% wt Pd and 7% wt Cu on carbon, whichwas reduced prior to the experiment at 180° C. under hydrogen at 10 bargfor 1 hour, was introduced into the reaction mixture and hydrogen wasfed into the reactor until a pressure of 70 barg was reached. Themixture was heated to 100° C. and was kept at this temperature underconstant stirring (900 rpm) for 1 hour. The exact same procedure wasperformed with a 5% Pd on carbon catalyst, which was not pre-reduced.

The results are reported in the following table:

Selectivity (%) Catalyst Conversion (%) 4-Br-BDMA BDMA Others Pd/C 99.80.4 88.0 11.6 Pd/Cu on C 99.72 80.7 16.0 3.3 Legend (further to thesymbols defined herein above): 4-Br-BDMA 4-bromo-benzyl dimethylamine

Example 9 Reductive amination of 2-bromo-benzaldehyde to 2-bromo-benzyldimethylamine

Methanol (27 g), ortho-bromo-benzaldehyde (2-Br-BZA, 90 g) anddimethylamine (DMA, 37 g) were introduced into a 300 ml high pressurereactor. Dimethylamine was introduced by connecting the autoclave with abomb containing liquid DMA. Nitrogen was fed into the reactor until apressure of 10 barg was reached. The mixture was heated to 80° C. andwas kept at this temperature under constant stirring (450 rpm) for 1hour. The mixture was cooled to room temperature and the reactor wasvented. The catalyst, containing 3% wt Pd and 7% wt Cu on carbon, whichwas reduced prior to the experiment at 180° C. under hydrogen at 10 bargfor 1 hour, was introduced into the reaction mixture and hydrogen wasfed into the reactor until a pressure of 70 barg was reached. Themixture was heated to 100° C. and was kept at this temperature underconstant stirring (900 rpm) for 15 minutes. The exact same procedure wasperformed with a 5% Pd on carbon catalyst, which was not pre-reduced.

The results are reported in the following table:

Selectivity (%) Catalyst Conversion (%) 2-Br-BDMA BDMA Others Pd/C 74.825.5 58.3 16.2 Pd/Cu on C 73.2 81.3 8.4 10.3 Legend (further to thesymbols defined herein above): 2-Br-BDMA 2-bromo-benzyl dimethylamine

Example 10 Comparison of catalysts for the reductive amination of2-chloro-benzaldehyde with DMA to produce 2-Cl-BDMA

Amination Step:

2-Chloro-benzaldehyde (2-Cl-BZA) and methanol (0.3 g/g 2-Cl-BZA) wereadded to a 100 ml high pressure reactor. The reactor was closed anddimethylamine (DMA) (1.3 equivalents based on 2-Cl-BZA) was added usinga solution of DMA in methanol (2M). The mixture was stirred (1500 rpmwith hollow shaft stirrer) at 75° C. under 10 barg of nitrogen for 1hour. Then the reactor was cooled down and the pressure released.

Hydrogenolysis Step:

The selected catalyst (3 mg total weight of catalyst per gram of2-Cl-BZA) was added to the reaction mixture of the amination step. Thereactor is purged three times with nitrogen and then the reactor was putunder hydrogen pressure of 70 barg. The reaction mixture was stirred(1500 rpm with a hollow shaft stirrer) and heated up to 100° C. After 15minutes the reactor was cooled down and flushed with nitrogen. Thecatalyst was filtered off and the sample was analysed by gaschromatography (GC).

In this example, a monometallic Pd-on-C catalyst was compared with abimetallic Pd/Cu on C catalyst, first as such and a second time afterhaving been heat treated prior to its use in the example.

The results are reported in the following table:

Conversion Selectivity (%) (%) after 15 2Cl- 2-Cl- Catalyst minutes BDMABDMA BDMA BOH Others 5% Pd on C 99.9 45.8 33.4 Nd 0.15 20.65 3% Pd—7%98.3 1.5 96.2 Nd 2.1 Nd Cu on carbon 3% Pd—7% 97.6 0.2 99.3 Nd 0.1 Nd Cuon carbon, calcined under N2 (*) (*): The calcination or heat treatmentcomprised a calcination in a tubular furnace in nitrogen flow (30ml/min) at 400° C. for 2 hours. The symbols in this table are the sameas in Examples 2 and 3 above. The 3% Pd—7% Cu on carbon was produced asdescribed in Example 3. The monometallic 5% Pd on carbon catalyst wasobtained as a commercial catalyst offered by the company Evonik, as inall the examples.The analytical techniques used in this example had a higher detectionlimit compared to the preceding examples. This explains why certaincomponents which could be found in the preceding examples, stayed belowthe detection limit in this example.

Example 11 Investigation of Different Bimetallic Systems

The same reaction was performed as in Example 10, following exactly thesame experimental protocol but with different kind of catalysts, inparticular Pd/Au, Pd/Ni, Pd/Ag, and Pd/Fe.

The catalysts were prepare by impregnating the monometallic Pd catalystfrom Example 10 respectively with NaAuCl₄, Ni(NO₃)*6H₂O, AgNO₃, andFe(NO₃)₃*9H₂O. In more detail: 0.5 g of the monometallic Pd catalyst wasdispersed in 50 ml of distilled water. A metal precursor solutioncontaining 5×10⁻² molar of the selected second metal (M) precursorcompound was added to the dispersion under vigorous stirring. Thecatalyst was filtered and washed several times with water. The materialobtained was then suspended in distilled water and a freshly preparedsolution of NaBH4 (0.1 molar) was added under vigorous stirring at roomtemperature. The sample was filtered, washed and dried at 80° C. for 4hours. In all the cases the ratio of Pd/M was 1:2 wt/wt and thequantitative adsorption was checked by Atomic Adsorption.

The results are reported in the following table:

Con- version Catalyst (all (%) Selectivity (%) on carbon after 15 2Cl-2-Cl- support) minutes BDMA BDMA BDMA BOH Others 3% Pd—7% 98.3 1.5 96.2Nd 2.1 Nd Cu 5% Pd—10% 95.6 2.9 96.2 0.8 Nd Nd Au 5% Pd—10% 80.6 1.097.9 Nd 1.0 Nd Ni 5% Pd—10% 72.2 Nd 98.9 Nd 1.0 Nd Ag

All the bimetallic catalysts showed good activity and good selectivityto 2-Cl-BDMA. In particular the Pd/Ag catalyst showed a higherselectivity that the catalyst having 3% Pd and 7% Cu.

Example 12 Reductive amination of benzaldehyde with 2-Cl-aniline

The experimental protocol was identical to this of Example 10, exceptthat different starting materials were used, and as catalysts were usedthe commercial monometallic 5% Pd-on-C catalyst and the 3% Pd-7% Cu oncarbon catalyst which was used in several of the preceding examples.

The results are reported in the following table:

Selectivity (%) Catalyst Conversion (%) N-B, 2-Cl-aniline N-B anilineOthers Pd/C 68 27.3 66.5 6.2 Pd/Cu on C 22 58.3 33.5 8.2 Legend (furtherto the symbols defined herein above): N-B, 2-Cl-aniline N-benzyl,2-Chloro-aniline N-B aniline N-benzyl aniline

Having now fully described this invention, it will be appreciated bythose skilled in the art that the invention can be performed within awide range of parameters within what is claimed, without departing fromthe scope of the invention, as defined by the claims.

The invention claimed is:
 1. A process for the reductive amination of ahalo-benzaldehyde in the presence of a nitrogen containing compound,wherein the halogen atom is selected from the list consisting ofchlorine, bromine, iodine, and combinations thereof, in the presence ofhydrogen and a heterogeneous catalyst supported on carbon, saidheterogenous catalyst comprising at least one first metal comprisingpalladium, rhodium, or ruthenium, together with at least one secondmetal comprising silver, nickel, cobalt, tin, copper, or gold.
 2. Theprocess according to claim 1, wherein the nitrogen compound is selectedfrom ammonia, a primary amine, a secondary amine, and mixtures thereof.3. The process according to claim 1, wherein the reductive amination isperformed in two steps, in the first step reacting the aldehyde with thenitrogen containing compound, and in the subsequent step introducinghydrogen and the catalyst.
 4. The process according to claim 1, whereinthe heterogeneous catalyst comprises the first metal at a concentrationin the range of 0.1-10.0% by weight, based on the total weight of thecatalyst and the second metal at a concentration in the range of0.05-40% by weight, based on the total weight of the catalyst.
 5. Theprocess according to claim 1, further comprising the step of putting thefirst metal onto the carbon support by precipitation and putting thesecond metal onto a support by precipitation, at the same time asputting the first metal onto the support or after having put the firstmetal onto the support.
 6. The process according to claim 1, wherein theheterogeneous catalyst has been heat treated prior to its use in theprocess, at a temperature in the range of 50-500° C. wherein the heattreatment is performed for at least 2 hours.
 7. The process according toclaim 1, wherein the heterogeneous catalyst comprises the first metaland the second metal in a weight ratio of the second metal relative tothe first metal in the range of 0.05:1.0 to 10.0:1.0.
 8. The processaccording to claim 1, wherein the heterogeneous catalyst has a metalarea, as measured by carbon monoxide chemisorption of at least 3.0 m2/g.9. The process according to claim 1, wherein the heterogeneous catalysthas been pre-reduced prior to its use in the process.
 10. The processaccording to claim 1, wherein the reductive amination is performed at aH2 partial pressure in the range of 0.01-250 bar gauge and at atemperature in the range of 0-300° C.
 11. The process according to claim1, wherein the process is performed in continuous mode.
 12. The processaccording to claim 1, wherein the reductive amination is performed inthe presence of a solvent.
 13. The process according to claim 1, whereinreaction products of said process compriseortho-chloro-benzyldimethylamine and wherein the process furthercomprises preparing a Grignard reagent from said ortho-chloro benzyldimethyl amine, and further subjecting the Grignard reagent to aGrignard reaction.
 14. The process according to claim 1, wherein thereaction products comprise ortho-chloro-benzyldimethylamine, furthercomprising converting said ortho-chloro-benzyldimethylamine tochloromethylphenylglyoxylic ester.
 15. The process according to claim14, wherein said chloromethylphenylglyoxylic ester is converted to amethoximinophenylglyoxylic ester.
 16. The process according to claim 1,wherein said halo-benzaldehyde comprises ortho-chlorobenzaldehyde,meta-chlorobenzaldehyde, or para-chlorobenzaldehyde.
 17. The processaccording to claim 1, wherein said amine compound comprises a secondaryamine.
 18. The process according to claim 1, wherein said heterogeneouscatalyst comprises a first metal comprising palladium and a second metalcomprising silver, copper, nickel, or cobalt.
 19. The process accordingto claim 1, wherein the halogen atom on said halo-benzaldehyde compriseschlorine, and after conversion of said halo-benzaldehyde, at least 95%of the halo-benzaldehyde retains said chlorine atom.
 20. The process ofclaim 19, wherein at least 98% of the halo-benzaldehyde retains saidchlorine atom after conversion.
 21. The process according to claim 1,wherein said halo-benzaldehyde comprises ortho-chlorobenzaldehyde, saidamine compound comprises a secondary amine, and said heterogeneouscatalyst comprises a first metal comprising palladium and a second metalcomprising silver, copper, nickel, or cobalt.
 22. The process accordingto claim 1, wherein the process generates a reaction product compositioncomprising 2-chloro-benzyl-dimethylamine.
 23. The process of claim 22,wherein the process generates at least 98.5 wt. %2-chloro-benzyl-dimethylamine based on the weight of the reactionproduct composition, not including, if present, water, methanol anddimethylamine.
 24. The process of claim 23, wherein the processgenerates at least 99.1 wt. % 2-chloro-benzyl-dimethylamine.
 25. Theprocess of claim 22, wherein the reaction products do not contain morethan 0.04 wt. % 2-chloro-dichloromethyl benzene, not more than 1.0 wt. %2-chloro-benzyl alcohol, not more than 0.20 wt. % 2-chloro-benzaldehyde,and not more than 0.40 wt. % benzyl dimethyl amine, each based on theweight of the reaction product composition, not including, if present,water, methanol and dimethylamine.
 26. The process of claim 25, whereinthe amount of benzyl dimethyl amine is not more than 0.20 wt. %.
 27. Theprocess of claim 1, wherein the carbon support comprises activatedcarbon.
 28. The process of claim 4, wherein the carbon support comprisesactivated carbon.
 29. The process of claim 12, wherein the carbonsupport comprises activated carbon.
 30. The process of claim 18, whereinthe carbon support comprises activated carbon.
 31. The process of claim19, wherein the carbon support comprises activated carbon.
 32. Theprocess of claim 25, wherein the carbon support comprises activatedcarbon.
 33. The process according to claim 6, wherein the heat treatmentis performed for at least 3 hours.
 34. A process for the reductiveamination of a halo-benzaldehyde in the presence of a nitrogencontaining compound at a halo-benzaldehyde conversion of at least 73.2%and a selectivity to a halo-benzylamine of at least 81.3%, wherein thehalogen atom is selected from the list consisting of chlorine, bromine,iodine, and combinations thereof, in the presence of hydrogen and aheterogeneous catalyst supported on carbon comprising at least one firstmetal comprising palladium, rhodium, or ruthenium, together with atleast one second metal comprising silver, nickel, cobalt, tin, copper,or gold.
 35. The process according to claim 34, wherein the nitrogencompound comprises a secondary amine.
 36. The process according to claim34, wherein the heterogeneous catalyst comprises the first metal at aconcentration in the range of 0.1-10.0% by weight, based on the totalweight of the catalyst and the second metal at a concentration in therange of 0.05-40% by weight, based on the total weight of the catalyst,and the catalyst has a metal area, as measured by carbon monoxidechemisorption of at least 0.5 m2/g.
 37. The process according to claim34, wherein the heterogeneous catalyst has been heat treated, preferablyat a temperature in the range of 50-500° C., the heat treatment beingperformed for at least 2 hours.
 38. The process according to claim 34,wherein the reductive amination is performed at a H2 partial pressure inthe range of 0.01-250 bar gauge and at a temperature in the range of0-300° C.
 39. The process according to claim 34, wherein the process isperformed in continuous mode.
 40. The process according to claim 34,wherein the reductive amination is performed in the presence of asolvent.
 41. The process according to claim 34, wherein reactionproducts of said process comprise ortho-chloro-benzyldimethylamine andwherein the process further comprises preparing a Grignard reagent fromsaid ortho-chloro benzyl dimethyl amine, and further subjecting theGrignard reagent to a Grignard reaction.
 42. The process according toclaim 34, wherein said heterogeneous catalyst comprises a first metalcomprising palladium and a second metal comprising silver, copper,nickel, or cobalt.
 43. The process according to claim 34, wherein thehalogen atom on said halo-benzaldehyde comprises chlorine, and afterconversion of said halo-benzaldehyde, at least 95% of thehalo-benzaldehyde retains said chlorine atom.
 44. The process of claim30, wherein at least 98 wt.% of the halo-benzaldehyde retains saidchlorine atom after conversion.
 45. The process according to claim 34,wherein said halo-benzaldehyde comprises ortho-chlorobenzaldehyde, saidamine compound comprises a secondary amine, and said heterogeneouscatalyst comprises a first metal comprising palladium and a second metalcomprising copper, nickel, or cobalt.
 46. The process of claim 34,wherein the process generates at least 98.5 wt.%2-chloro-benzyl-dimethylamine based on the weight of the reactionproduct composition, not including, if present, water, solvent anddimethylamine.
 47. The process of claim 46, wherein the processgenerates at least 99.1 wt.% 2-chloro-benzyl-dimethylamine.
 48. Theprocess of claim 34, wherein said halo-benzaldehyde comprisesortho-chlorobenzaldehyde, said amine compound comprises a dimethylamine, and reaction products of the process do not contain more than0.04 wt.% 2-chloro-dichloromethyl benzene, not more than 1.0 wt.%2-chloro-benzyl alcohol, not more than 0.20 wt.% 2-chloro-benzaldehyde,and not more than 0.40 wt.% benzyl dimethyl amine, each based on theweight of the reaction product composition, not including, if present,water, solvent and dimethylamine.
 49. The process of claim 48, whereinthe amount of benzyl dimethyl amine is not more than 0.20 wt.%.
 50. Theprocess according to claim 34, wherein the conversion is at least 75%and the selectivity is at least 96.4%.
 51. The process according toclaim 34, wherein the conversion is at least 95.6% and the selectivityis at least 96.2%.
 52. The process according to claim 34, wherein theconversion is at least 98.3% and the selectivity is at least 96.2%. 53.The process according to claim 34, wherein the conversion is at least80.6% and the selectivity is at least 97.9%.
 54. The process accordingto claim 34, wherein the conversion is at least 99.9% and theselectivity is at least 98.25%.